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Invisible communities inhabit every nook, crevice and niche of the globe, from our own bodies to the soil under our feet and the houses in which we live. These are the microbiomes that silently help to maintain a careful balance in our bodies and the environment. They are communities of bacteria, fungi, viruses, bacteriophage and protozoa and each is well suited to specific conditions. The microbiome in our mouth for example will be very different to that in our gut.
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he term “microbiome” first appeared in scientific literature in 1988. However, it is only relatively recently that we have started to gain a more comprehensive understanding of what microbiomes are, how they work, their importance and the wider impact they have on health and disease. It is no coincidence that this leap in knowledge has coincided with technological improvements, especially in genome interrogation.
But why is our microbiome important? Under “normal” conditions, a healthy balance of microbial species facilitates important functions, like digestion and keeps pathogenic species at bay, but in return we have to look after them. Imbalanced diets and overuse of antimicrobials inside and outside the body can all contribute to the depletion of important species, upsetting the delicate balance. The same is true of soil, intensive farming and overuse of chemicals can negatively impact soil microbiomes and consequently plant and invertebrate health too. Analyzing the species present can be a useful indicator of health issues and their unique compositions can also be helpful to forensic scientists.
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rior to the "genomic era", scientists relied on microscopy, cell culturing and pulse-field gel electrophoresis to study microbes. Modern DNA sequencing technologies now permit a more detailed look into the "microbial world" at the genetic level, helping us to understand who is there and what they are doing.
Two key approaches are adopted here: 16S ribosomal RNA (rRNA) sequencing and shotgun metagenomics. The former, a type of amplicon sequencing, is a more traditional approach that utilizes a region of the 16S rRNA gene found in all bacteria and archaea. This gene comprises eight highly conserved regions and nine variable regions. When sequenced, polymorphisms in the variable region of the gene can be detected, enabling researchers to identify and classify diverse microbes in a sample by comparing the sequencing data against a database of strains with known taxonomic identity. It tells us who is there. Whilst commonly adopted, this approach is not without its limitations: the quality of the data stored in public databases can adversely affect study outcomes and distinguishing between sequencing errors and natural genetic variations can be tricky.
The latter approach, shotgun metagenomics, adds an extra level of information, telling us who is there and what they are doing. DNA is extracted from all the cells in a sample and sheared randomly into smaller pieces that are sequenced independently, thereby limiting bias. Overlapping regions of the fragments that have been sequenced independently are used to piece together the puzzle and reconstruct both the genomes and partial genomes that are present in the sample. Shotgun metagenomics data is complex to analyze, and there are three common approaches to quantify diversity: marker gene analysis, binning and assembling sequences into distinct genomes. The data obtained from metagenomic sequencing relies heavily on the bioinformatic tool capabilities available to each researcher, and it can be time-consuming.
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nteractions between the microbiota and the host play a key role in several biological processes, such as nutrition and metabolism. However, the intricate and intertwined nature of the microbiome–host relationship also carries risks in terms of the development and progression of human disease. Here, we take a closer look at the microbiome’s role in health and disease – and highlight its potential as a diagnostic tool and therapeutic strategy.
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ver the past decade, there has been increasing interest in the microbiome and cancer – between 2005 and 2015 the number of published articles on the microbiome and cancer increased by almost 2000%. As well as highlighting the direct link between cancer and a host’s microbiota, these studies have also provided evidence that microbes can impact cancer immunotherapy response.
Numerous studies have shown a pathological imbalance in the gut microbiome of patients diagnosed with colorectal cancer. Whilst several bacteria have been linked to colorectal cancer, for example species of; Fusobacterium,
Peptostreptococcus,
Porphyromonas,
Prevotella,
Parvimonas,
Bacteroides and Gemella, in many cases the underlying mechanisms driving carcinogenesis are yet to be elucidated. Certain species of oral bacteria have been linked to an increased risk of developing pancreatic cancer. A study conducted by researchers from the NYC Langone Medical Center found that the presence of Porphyromona gingivalis in oral wash samples was linked to a 59% increased risk of developing pancreatic cancer. In addition, the presence of Aggregatibacter actinomycetemcomitans was associated with a 119% increased risk.
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he microbiome has come under intense scrutiny by neuroscientists in the last decade. This has been driven by an explosion of data connecting gut bacteria to diseases of the brain and an improved appreciation of how our brain communicates with nerve cells in our gut. Advances in our ability to sequence the microbiome has allowed neuroscientists to link microbiome signatures to different brain diseases.
Parkinson’s disease, a neurodegenerative condition defined by gradually increasing motor deficits, is also associated with a battery of gastrointestinal symptoms. Researchers studying a rodent model of the condition noted that adding microbiota taken from Parkinson’s patients accelerated the rodents’ motor impairments, whilst microbiota from healthy controls did not. A 2018 study showed that in Parkinson’s patients, decreased Lachnospiraceae and increased Lactobacillaceae and Christensenellaceae were linked to more severe clinical signs. Further links to the microbiota have been noted in autism spectrum disorder, Alzheimer’s disease and ischemic stroke. Nevertheless, convincing evidence in humans showing a causative element to these links has remained elusive and much of the current data is hard to compare and inconsistent.
Theorized mechanisms of causation revolve around molecules secreted by microbes that might impact the enteric nervous system or the brain. Bacterial fermentation in the gut leads to the production of short-chain fatty acids (SCFAs). The presence of SCFAs in cerebrospinal fluid (CSF) has been widely recognized and preclinical evidence suggests that SCFAs may act to strengthen the integrity of the blood–brain barrier, the breakdown of which is a hallmark of several neurodegenerative conditions. Future research into the brain–gut–microbiome (BGM) axis will need to tease out proposed causative links in more detail. The recent discovery of microbial populations within the Alzheimer’s post-mortem brain illustrates that the connection between our microbiome and our nervous system is far from fully understood.
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n increasing number of studies have identified that specific species and levels of microbes are associated with the presence of a particular disease or condition. These microbial signatures could be harnessed to help diagnose diseases earlier and more accurately.
For example, a team of researchers from the European Molecular Biology Laboratory were able to identify taxonomic markers that distinguished colorectal cancer patients from tumor-free patients. By performing metagenomic sequencing on fecal samples, they were able to detect cancer-associated changes in the fecal microbiome. Other studies have shown that fecal microbial signatures also have the potential to help non-invasively diagnose and monitor several other diseases, including predicting non-alcoholic fatty liver disease-cirrhosis and evaluating inflammatory bowel disease severity.
Microbiome-based diagnostics are not only limited to the gut. Saliva is rich in microbes, with more than 700 species of bacteria inhabiting the oral cavity. Swabbing and mouthwash samples make the oral microbiome easily accessible and an attractive target for diagnostics. The diversity and levels of bacteria present in saliva can be an indicator of conditions ranging from dental caries to oral and gastrointestinal cancer.
As the largest organ and first barrier of the human body, the skin is also home to a wide variety of microbes that could be detected and monitored to provide diagnostic and prognostic information. Investigations are ongoing into how the skin microbiome could be leveraged to diagnose and guide the treatment of cutaneous conditions such as acne, psoriasis and wound healing.
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he microbiome can, in some cases, help a host fight disease. For example, researchers recently discovered that specific bacteria present within the gut microbiota can help a patient’s immune system mount an anti-tumor response. A recent study published in Science showed that by combining immunotherapy with a specific microbial therapy it was possible to “boost” the immune response against certain melanoma, bladder and colorectal cancers.
As well as directly harnessing the microbiota as a therapeutic, researchers have been examining the microbiomes of various organisms in an attempt to identify promising bioactive compounds with anticancer properties. For example, Murray, et al. have been studying the microbiota of an Antarctic ascidian called Synoicum adareanum to determine the bacteria comprising the core microbiome. With this information they hope to identify which of the bacteria are producing palmerolide – a bioactive compound that holds promise as a melanoma-specific drug.
There has been mounting interest in the development of living therapeutics, whereby bacteria are altered to produce therapeutic compounds. A strain of Escherichia coli has been engineered to produce specific proteins needed to treat rare metabolic deficiencies. In addition, a team from Singapore has engineered gut bacteria so that they can associate with colon cancer cells and secrete an enzyme that converts glucosinolates, substances naturally found in some vegetables, into sulphoraphane, an organic small molecule with known anticancer activity. A study published in Nat Commun. describes the modification of a gut bacterium commonly used as a probiotic so that it can detect signals emitted by pathogenic bacteria – and synthesize an antimicrobial molecule in response to the signals.
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